Global Characterization of Protein Palmitoylation in Trypanosomes Palmitoylation is a posttranslational modification of proteins that can affect how a protein interacts with lipids and proteins in a membrane compartment. Dual aminoacylation with myristate and palmitate is essential for targeting of proteins to lipid rafts, and is a common feature of key molecules in cell signaling. While N- myristoylation is carried out in the endoplasmic reticulum by a single N-myristoyltransferase, S-palmitoylation, and rarely N-palmitoylation (occurring on an N-terminal cys residue), is mediated by one of a number of palmitoyl acyltransferases (PATs), each having its own localization and substrate specificity. S-palmitoylation is essential for the functions of a number of important proteins and is essential in eukaryotes. Thus, the identification and linkage of specific PATs and their substrates constitutes a unique approach to systematic analysis eukaryote biology. In the African trypanosome, Trypanosoma brucei, our LC-MS/MS and RNAi data strongly suggest that protein palmitoylation is an abundant and important modification. In the proposed project, we will conduct a global analysis of protein palmitoylation in T. brucei in a five-year intensive research effort that will determine the palmitoylproteomes of T. brucei, identify the substrate profiles and functions of T. brucei PATs, and investigate this class of enzymes as potential targets for trypanocidal chemotherapy.

Public Health Relevance

Global Characterization of Protein Palmitoylation in Trypanosomes Protein modification by palmitoylation is essential in eukaryotes. In the African trypanosome, Trypanosoma brucei, protein palmitoylation is an abundant and essential modification. We will characterize, in a comprehensive manner, protein palmitoylation in T. brucei, and identify the palmitoylating enzymes that are important for specific cellular processes and protein targeting. Further, we will systematically link each palmitoyl protein with its transferase, which has not been accomplished in any system and will significantly advance the field generally. Because palmitoylation is essential, T. brucei-specific palmitoyl acyltransferases are novel drug targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM102689-02
Application #
8685282
Study Section
Special Emphasis Panel (ZRG1-IDM-M (02))
Program Officer
Chin, Jean
Project Start
2013-07-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$366,633
Indirect Cost
$101,643
Name
Northwestern University Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Goldston, Amanda M; Sharma, Aabha I; Paul, Kimberly S et al. (2014) Acylation in trypanosomatids: an essential process and potential drug target. Trends Parasitol 30:350-60